In previous articles on Geert Vanden Bossche's Voice for Science and Solidarity I described numerous phytochemicals that epigenetically and metabolically reprogramme innate immune cells to create a ‘memory’ of a pathogen, as a priming tool for an improved host response (2).
“The best place to find God is in a garden. You can dig for him there”. George Bernard Shaw (1)
As the effects of the phytochemicals in herbal medicines are multiple and pleiotropic (produce more than one) as described also, herbal medicines are immunomodulating agents. In this article I aim to describe the phytochemicals that block severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) host cell entry to prevent infection. Bear in mind, that these phytochemicals also train immunity. One stone, many birds.
SARS-CoV-2 cell entry mechanisms
The unprecedented public health and economic impact of the coronavirus disease 2019 (COVID-19/C-19) pandemic caused by SARS-CoV-2 infection triggered an unprecedented scientific response. Much of this response focused on researching the mechanisms of SARS-CoV-2 entry into host cells, in particular, how the receptor-binding domain (RBD) of the spike (S) protein binds to its receptor, angiotensin-converting enzyme 2 (ACE2). The processes that facilitate efficient human transmission RBD-ACE2 complexes which allows SARS-CoV-2 to enters host cells is multistep. Each of these steps may lead to potential therapeutic targets. The roles of the human proteases, furin-like proteases, transmembrane protease serine 2 (TMPRSS2) and cathepsin L in these processes have been elucidated (3).
RBD-ACE2 complex inhibition
As mentioned in previous articles, SARS-CoV-2 uses host cell receptor ACE2 to overcome the barrier and bind to host cells in the alveoli, thus ACE2 is a therapeutic target to treat C-19 (26). Surface S proteins located on the coronavirus (CoV) surface help mediate CoV entry into human host cells. SARS-CoV-2 S protein binds to its host-cell receptor ACE2 protein through its RBD, therefore, both RBD and ACE2 are therapeutic targets to prevent SARS-CoV-2 and treat C-19 disease (4).
Elderberry fruit and flower (Sambucus nigra/ Jie Gu Mu) extracts inhibit SARS-CoV2 S-protein RBD and ACE2 (5). The phytochemical triterpenoids such as glycyrrhetinic and oleanolic acids reduce the RBD-ACE2 binding (6). Glycyrrhetinic acid, a product of glycyrrhizic acid, is extracted from liquorice root (Glycyrrhiza glabra/ Gan Cao). The most important sources of oleanolic acid in the human diet are olive (Olea europaea/ Qing Guo) fruits and oil, from which the phytochemical derives its name (7). Additional sources of oleanolic acid include thyme (Thymus vulgaris), clove, apple, loquat, grape, and sage (Salvia officinalis) (8). Jujube fruit or Chinese red date (Ziziphus jujuba/ Hong Zao), whorled rosinweed (Silphium trifoliatum), rosinweed (Silphium integrifolium), and ginseng (Panax spp/ Ren Shen) are also good sources of oleanonic acid (9, 10).
A comparative study investigating the antioxidant properties and phenolic contents (total phenols, flavonoids, flavonols and proanthocyanidins), and ACE inhibitory activities of selected herbal extracts, found that Indian gooseberry (Phyllanthus emblica/ Yu Gan Zi ) has the strongest ACE inhibition potential followed by withania (Withania somnifera/ Nan Fei Zui Jia), roselle (Hibiscus sabdriffa/ Mei Gui Qie), ginkgo (Ginkgo biloba/ Yin Xing Ye), holy basil/tulsi (Ocimum sanctum/ Sheng Lou Le) and garlic (Allium sativum/ Du Xuan) (11). The major green tea polyphenol epigallocatechin gallate (EGCG) effectively blocks viral attachment of SARS-CoV-2 and new variants to host cells by inhibiting S binding to ACE2 receptor (12).
Sequence analysis indicates that the novel CoV has an insertion of a furin cleavage site (PRRAR) in its S protein. Furin cleavage site plays a critical role in SARS-CoV-2 replication and pathogenesis (13). Furin protease inhibitors may be promising antiviral agents for prevention of SARS-CoV-2 infection and treatment of C-19. Comorbidities associated with C-19 including obesity, diabetes, and hypertension are associated with increased circulating furin levels, therefore addressing comorbidities through diet and lifestyle modifications, and pharmacological treatment is indicated to reduce C-19 pathogenicity. Natural furin inhibitors may prove highly useful to inhibit viral entry and propagation (14). Natural furan inhibitors include the phytochemicals andrographolide and neoandrographolide from andrographis (Andrographis paniculate) and the flavonoid baicalein from Scutellaria baicalensis. Additionally, the tetrahydroxyflavone luteolin exhibited uncompetitive inhibition of human furin in in vitro studies (15).
In addition to SARS-CoV-2 engaging ACE2 as the entry receptor, SARS-CoV-2 also uses transmembrane serine protease 2 (TMPRSS2) for S priming (16). As a priming agent of SARS-CoV-2, TMPRSS2 inhibitors potently block SARS-CoV-2 viral entry and protect human epithelial lung cells making TMPRSS2 inhibitors a therapeutic target for C-19 (17). Furthermore, SARS-CoV-2-infected cells express the S protein at their surface and fuse with ACE2-positive adjoining cells. Expression of S protein without any other viral proteins triggers syncytia formation. Syncytia are a defining pathological feature of C-19 and is considered a frequent feature of severe C‐19 (18). SARS-CoV-2 emerging variants display enhanced S-mediated syncytia formation (19). Interferon-induced transmembrane proteins (IFITMs) block the entry of many viruses and inhibit S-mediated fusion. IFITM1 is considered more active than IFITM2 and IFITM3, with IFITM1 restricting replication of viruses that enter cells via the plasma membrane (20). TMPRSS2 enhances infectivity of cell-free virions, processes both S and ACE2, and accelerates the fusion process to increase syncytia formation. TMPRSS2 inhibits the antiviral effect of IFITMs (21).
Effective natural TMPRSS2 inhibitors include a Berberis species flavonolignan similar to silymarin, the green tea polyphenol EGCG and the aromatase inhibitor isogemichalcone B derived from the paper mulberry (Broussonetia papyrifera). Ayurvedic traditional medicine derived phytochemicals 7-hydroxy-14-deoxywithanolide U from ashwagandha (Withania somnifera), and (6R,9R)-roseoside from basil (Ocimum basilicum) and holy basil/tulsi (Ocimum sanctum) also act as effective natural TMPRSS2 inhibitors (22). The alkaloid berbamine hydrochloride (BBH) isolated from traditional Chinese medicine Amur barberry (Berberis amurensis) acts a natural syncytium inhibitor by blocking virus entry through inhibiting the S-mediated cell-cell fusion (23).The phytochemical glycyrrhizin (GR) effectively inhibits SARS-CoV-2 replication. In silico docking studies reported that GR may directly interact with not only host TMPRSS2 but also other key players in viral transmission and replication such as ACE2, S protein, and 3C-like protease (3CLpro), also known as viral main protease (Mpro) (38, 39). In silico identification of potential phytochemical human proteases inhibitors from Indian herbal medicines found 96 inhibitors of TMPRSS2. The three top inhibitors of TMPRSS2 were qingdainone from Assam indigo or Chinese rain bell (Strobilanthes cusia), edgeworoside C from Nepali paper bush (Edgeworthia gardneri) and adlumidine from pitpapra (Fumaria indica) (24).
Cathepsin L inhibition
Like TMPRSS2, the human protease cathepsin L also play a key role in host cell entry of SARS-CoV-2. In silico identification of potential phytochemical human proteases inhibitors from Indian herbal medicines found nine natural inhibitors of cathepsin L. The three top inhibitors of cathepsin L were the phytochemicals, ararobinol from coffee senna (Senna occidentalis), (+)-oxoturkiyenine from nodding hypecoum (Hypecoum pendulum) and 3α,17α-cinchophylline from Peruvian bark (Cinchona calisaya) (24).
RBD comparisons of the structures of three CoVs have shown that there is a high affinity between human MERS-CoV receptor dipeptidyl peptidase 4 (DPP4) and the spike RBD of SARS-CoV-2, thus DPP4 is also recognised as a candidate binding target of the SARS-CoV-2 S protein (25). DPP4, also known as the T-cell antigen CD26, acts as a CoV coreceptor, having a mechanism similar to the host cell entry of SARS-CoV-2 and is another potential therapeutic target. DPP4 inhibitors known as gliptins are widely used in diabetes patients and whilst the role of DPP4 inhibitors in SARS-CoV-2 infection remains to be clarified, evidence suggests that DPP4 inhibitors modulate inflammation and exert anti-fibrotic activity and that these properties may useful to stop the progression of the hyperinflammatory state associated with severe C-19 (26). Additionally, DPP4 inhibition enhances lymphocyte trafficking via chemokine interferon-γ inducible protein 10 kDa (CXCL10) cleavage, improving both naturally occurring tumour immunity and immunotherapy (27).
DPP4 inhibitors could be implicated in endothelial, neutrophil and monocyte/macrophage mediated immunity and research with DPP4 inhibitors in the context of the C-19 pandemic is warranted. The phytochemical flavonoids luteolin, apigenin and flavone are potent DPP4 inhibitors. (28). Oregano (Origanum vulgare), thyme (Thymus vulgaris) and juniper berries (Juniperus communis) contain the highest sources of luteolin (29). Apigenin is found at significant amounts in parsley, chamomile (Matricaria chamomilla L.), thyme, oregano, and basil (Ocimum basilicum) (30). Flavones are one of the important subgroups of flavonoids. Celery, parsley, red peppers, red cabbage, chamomile, mint (Mentha piperita L./Bo He) and ginkgo (Ginkgo biloba /Yin Xing Ye) are major sources of flavones (31).
Custer of differentiation 147 (CD147) is an alternative glycoprotein host cell receptor for SARS-CoV-2 infection in ACE2-deficient cell types. CD147 activates matrix metalloproteinases and promotes inflammation. CD147 is responsible for the cytokine storm in the lungs through the mediation of viral invasion (32). Despite lesser affinity towards C-19 virus when compared to ACE2, CD147 is a novel route for SARS-CoV-2 invasion and a major therapeutic target (33). CD147 is described as an immunoglobulin superfamily receptor. Within circulating immune cell populations, CD147 is highly expressed on activated T and B lymphocytes (specifically CD147 expression is detected in CD4+ and CD8+ T cells), the primary effector cells of the adaptive immune system. SARS-CoV-2 infects T lymphocytes through its S protein-mediated membrane fusion (34). CD147 is also highly expressed on dendritic cells, monocytes, macrophages and natural killer (NK) cells, the primary effector cells of the innate immune system (35, 36).
Melatonin acts as a natural CD147 inhibitor and can reduce the inflammatory pathway and help treat C-19 patients. Melatonin is reduced in the elderly and immune-compromised patients and should be considered as an adjuvant through its CD147 suppressor and immunomodulatory effects (32). Many medicinal plants contain high levels of melatonin. Pyrethrum maruna (Tanacetum parthenium L.) and St. John’s wort (Hypericum perforatum L.) Coffee beans, (Coffea sp.) goji berry /Gou Qi Zi, (Lycium barbarum L.), sweet cherries (Prunus avium L.), tart cherries (Prunus cerasus L.), white radish (Raphanus sativus L), ginger (Zingiber officinale), pomegranate (Punica granatum L) and Shungiku (Chrysanthemum coronarium L.) are all exceptionally high in melatonin. The Japanese pickle Kikumi is made from Chrysanthemum coronarium flower petals (37).
Heat shock protein/ GRP78 inhibition
In addition to ACE2 protein, cell surface heat shock protein A5 (HSPA5) act as another receptor that assists SARS-CoV-2 entry into host cells. HSPA5 is also called glucose-regulated protein 78 (GRP78). GRP78 is one member of the heat shock protein family of chaperone proteins. GRP78 is a host auxiliary factor for SARS-CoV-2 and GRP78 depleting antibody blocks viral entry and infection (38). GRP78 is predicted to bind to the RBD of the SARS-CoV-2 S protein (39). GRP78 forms a complex with SARS-CoV-2 S protein and host receptor ACE2 and is a potential therapeutic target to combat SARS-CoV-2 (40). Additionally, in the first CoV identified, infectious bronchitis virus (IBV), the RBD of IBV could interact with another heat shock protein member 8 (HSPA8) (41).
The green tea polyphenol EGCG inhibits GRP78. The bioactive phytochemical, hydroxytyrosol, in olive leaf (Olea europaea L.) shows good binding affinity to the GRP78 SBDβ in silico. Caffeic acid phenethyl ester (CAPE), found in the hive propolis of the honeybee, shows in silico binding affinity against GRP78. Black cumin seeds (Nigella sativa/ Hei Zhong Cao Zi). have a wide range of medical applications, however current interest is in their ability to disrupt S-mediated receptor-binding and entry of SARS-CoV-2 into cells. The phytochemical thymoquinone (TQ) is the main active ingredient of black cumin seed. Molecular docking studies have shown that TQ may inhibit the progression of C-19 by binding to the RBD on the SARS-CoV-2 S protein to hinder viral entry into cells. Molecular dynamics simulations have shown that TQ can interfere with the attachment of SARS‐CoV‐2 to host cells by binding to cell surface HSPA5 (GRP78), which is recognised by the viral S protein and upregulated upon viral infection. TQ also inhibits ACE2 receptors (42). Additionally, another phytochemical from black cumin seed, nigellimine, potentially inhibits viral entry into cells in two ways. Nigellimine enhances zinc entry into infected cells as well as inhibits virus uncoating inside infected cells (43).
Nonspecific virus entry inhibition
The S protein of SARS-CoV-2 S, which is used to enter cells, is a trimer with protomers, each composed of two subunits, S1 and S2. Chinese sumac (Rhus chinensis) luteolin and tetra-O-galloyl-β-d-glucose (TGG) specifically recognise the S2 subunit and binds to the SARS-CoV S-glycoprotein to prevent viral entry into host cells. Luteolin also binds to the S2 protein to exert its antiviral capacity by interfering with virus-cell attachment and consequent fusion. TGG and luteolin exhibit anti-SARS-CoV activities. The polyphenolic compound flavonoids, TGG and luteolin have been identified as displaying anti-SARS-CoV activities in wild-type SARS-CoV infection. TGG is isolated from the traditional Chinese medicine Indian gooseberry (Phyllanthus emblica/ Yu Gan Zi) (44). More than 200 Chinese medicinal herbal extracts were screened for antiviral activities against SARS-CoV. Four herbal extracts showed moderate anti-SARS-CoV activity. These herbal medicines were red spider lily (Lycoris radiate/ Shi Suan), sweet wormwood (Artemisia annua/ Qing Hao), large-lipped rustyhood (Pterostylis lingua) and Japanese evergreen spicebush (Lindera aggregate/ Wu Yao) (45). Other phytochemicals that have been found to act as SARS-CoV inhibitors include juglanin, found in green and black walnut husks (Juglans regia and Juglans nigra/ He Tao) and the catechins, catechin gallate (CG) and gallocatechin gallate (GCG) (46).
There are several molecular targets for C-19 that are being investigated for drug development and these can be matched using bioactive phytochemicals naturally occurring in herbal medicines. Many mechanisms exist, with many yet to be discovered. Each of these mechanisms is a potential therapeutic target for bioactive phytochemicals. In addition to herbal medicines having the potential to epigenetically and metabolically reprogramme innate immunity to train innate immune cells to remember, phytochemicals can act as molecular targets for C-19 and can potentially be used to prevent SARS-CoV-2 infection and protect at-risk populations. Many of these can be incorporated into our diet, or taken in herbal tincture or tablet form. For a herbal prescription see a qualified herbalist. Look out for my next article entitled, ‘Phytochemicals that Prevent SARS-CoV-2 Essential Proteins to Inhibit Virus Replication’. Sláinte! (Irish toast to good health).
Acute respiratory distress syndrome (ARDS)
Angiotensin-converting enzyme 2 (ACE2)
Angiotensin II (Ang II)
3-chymotrypsin-like protease (3CLpro)
Coronavirus disease 2019 (COVID-19/C-19)
Cluster of differentiation (CD)
Dipeptidyl peptidase 4 (DPP4)
Heat shock protein (HSP)
Interferon-induced transmembrane protein 1 (IFITM1)
Natural antibodies (NAb)
Natural killer (NK) cells
Nuclear factor-kappa B (NF-κB)
Receptor-binding domain (RBD)
Severe acute respiratory syndrome coronavirus 2 (SARS CoV 2)
Spike (S) protein
Transmembrane serine protease 2 (TMPRSS2)
Traditional Chinese medicines (TCMs)
Tumour necrosis factor alpha (TNF-α)
Viral main protease (Mpro)
Voice for Science and Solidarity (VSS)
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